The general anesthetic Isoflurane depresses synaptic vesicle exocytosis

被引:52
|
作者
Hemmings, HC
Yan, W
Westphalen, RI
Ryan, TA
机构
[1] Cornell Univ, Weill Med Coll, Dept Anesthesiol, New York, NY 10021 USA
[2] Cornell Univ, Weill Med Coll, Dept Pharmacol, New York, NY 10021 USA
[3] Cornell Univ, Weill Med Coll, Dept Biochem, New York, NY 10021 USA
关键词
D O I
10.1124/mol.104.003210
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
General anesthetics have marked effects on synaptic transmission, but the mechanisms of their presynaptic actions are unclear. We used quantitative laser-scanning fluorescence microscopy to analyze the effects of the volatile anesthetic isoflurane on synaptic vesicle cycling in cultured neonatal rat hippocampal neurons monitored using either transfection of a pH-sensitive form of green fluorescent protein fused to the luminal domain of VAMP (vesicle-associated membrane protein), (synapto-pHluorin) or vesicle loading with the fluorescent dye FM 1-43. Isoflurane reversibly inhibited action potential-evoked exocytosis over a range of concentrations, with little effect on vesicle pool size. In contrast, exocytosis evoked by depolarization in response to an elevated extracellular concentration of KCl, which is insensitive to the selective Na+ channel blocker tetrodotoxin, was relatively insensitive to isoflurane. Inhibition of exocytosis by isoflurane was resistant to bicuculline, indicating that this presynaptic effect is not caused by the well known GABA A receptor modulation by volatile anesthetics. Depression of exocytosis was mimicked by a reduction in stimulus frequency, suggesting a reduction in action potential initiation, conduction, or coupling to Ca2+ channel activation. There was no evidence for a direct effect on endocytosis. The effects of isoflurane on synaptic transmission are thus caused primarily by inhibition of action potential-evoked synaptic vesicle exocytosis at a site upstream of Ca2+ entry and exocytosis, possibly as a result of Na+ channel blockade and/or K+ channel activation, with the possibility of lesser contributions from Ca2+ channel blockade and/or soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated vesicle fusion.
引用
收藏
页码:1591 / 1599
页数:9
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